The contribution of IFN-g to the development and activity of disease in asthma has been debated for many years. IFN-g has been shown to both inhibit and exacerbate allergic airway inflammation. The goal of this proposal is to clarify how IFN-g functions in the regulation of allergic airway inflammation. Allergic airway inflammation is driven by Th2 cells, through the production of IL-4 and IL-13. IFN-g inhibits Th2-induced pathways by effects on IL-4/IL-13 signaling and IFN-g has hundreds of other pro-inflammatory effects that, under certain conditions, increase airway inflammation. We show that IFN-g inhibits Th2-induced responses in the respiratory tract, including having striking effects on mucus, eosinophilia and Th2 cell number in the airways. IFN-g also controls airway chitinase activity, a recently characterized, pro-inflammatory Th2 effector pathway in asthma. We have defined circumstances in which IFN-g is pro-inflammatory and leads to extensive neutrophilia. Our hypotheses are 1) IFN-g inhibits Th2 cytokine-dependent inflammatory pathways in the respiratory tract. 2) Anti-inflammatory effects of IFN-g are most prominent when low IFN-g levels are present in the airways and when Th1 cells/IFN-g are administered in the setting of ongoing Th2 inflammation, IFN-g enhances inflammation and neutrophilia. 3) IFN-g stimulates a distinctive pattern of cellular and molecular pathways in the regulation of mucus, chitinase and eosinophilia. The aims of this project are: AIM I. Define the cellular and molecular mechanisms of IFN-g inhibition of Th2 effector functions in the respiratory tract. AIM II. Determine the mechanism of IFN-g inhibition of eosinophilia and its relationship to the reciprocal induction of neutrophilia. AIM III. Determine how IFN-g regulates the number of Th2 cells in the respiratory tract.